Nm. Lehnert et al., Structure-based design of a bispecific receptor mimic that inhibits T cellresponses to a superantigen, BIOCHEM, 40(14), 2001, pp. 4222-4228
Key surface proteins of pathogens and their toxins bind to the host. cell r
eceptors in a manner that is quite different from the way the natural ligan
ds bind to the same receptors and direct normal. cellular responses. Here w
e describe a novel strategy for "non-antibody-based" pathogen countermeasur
e by targeting the very same "alternative mode of host receptor binding" th
at the pathogen proteins exploit to cause infection and disease. We have ch
osen the Staphylococcus enterotoxin B (SEB) superantigen as a model pathoge
n protein to illustrate the principle and application of our strategy. SEB
bypasses the normal route of antigen processing by binding as an intact pro
tein to the complex formed by the MHC class II receptor on the antigen-pres
enting cell and the T cell receptor. This alternative mode of binding cause
s massive IL-2 release and T cell proliferation. A normally processed antig
en requires all the domains of the receptor complex for its binding, wherea
s SEB requires only the alpha1 subunit (DR alpha) of the MHC class II recep
tor and the variable beta subunit (TCRV beta) of the T cell receptor. This
prompted us to design a bispecific chimera, DR alpha -linker-TCRV beta, tha
t acts as a receptor mimic and prevents the interaction of SEB with its hos
t cell receptors. We have adopted (GSTAPPA)(2) as the linker sequence becau
se it supports synergistic binding of DRa and TCRV beta to SEB and thereby
makes DR alpha-(GSTAPPA)(2)-TCRV beta as effective an SEB binder as the nat
ive MHC class II-T cell receptor complex. Finally, we show that DR alpha-(G
STAPPA)(2)-TCRV beta inhibits SEB-induced IL-2 release and T cell prolifera
tion at nanomolar concentrations.